What is causing the mortality in treating the anemia of chronic kidney disease: erythropoietin dose or hemoglobin level?

Purpose of Review: This article examines the potential mechanisms underlying adverse risk observed in four randomized controlled trials of anemia correction in chronic kidney disease (CKD) patients.
Recent Findings: The Normal Hematocrit Study, Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency, and Trial to Reduce Cardiovascular Events with Aranesp Therapy demonstrate increased risk of mortality and/or cardiovascular complications with targeting of a higher hemoglobin (Hb) in CKD patients. Although a higher Hb level was targeted in these trials, erythropoiesis-stimulating agent (ESA) exposure itself might account for the observed increased risk. This is because, in these trials, achieving a normal or near normal Hb was associated with improved survival and reduced cardiovascular risk. Indeed, it was the 'targeting' of a higher Hb with ESA that seemed to be the problem. Observational data, although conflicting, on the whole provide support for high dosage of ESA being harmful but cannot, by their very nature, prove causality.
Summary: After 20 years of ESA use, is it plausible that ESAs could be toxic? How does one reconcile conflicting observational data with a hypothesis that postulates ESA toxicity? Does the biology of erythropoietin provide a mechanistic explanation? The answers to these questions, among others, will be important in charting a future role for ESAs in treating CKD anemia.